Drug induced weight gain, an impediment to successful pharmacotherapy: focus on antipsychotics.

The antipsychotic drugs (APDs) are fundamental tools in current psychiatric practice. A new generation of agents, the atypical APDs, represents an important progress in the treatment of psychotic disorders. Unfortunately, some of them induce excessive body weight gain (BWG), obesity, hyperglycemia and dyslipidemia in the following order: clozapine approximately equal to olanzapine > quetiapine > risperidone > ziprasidone = aripiprazole. Appetite stimulation is probably the main mechanism of BWG and this is strongly correlated with the APD affinity for H1 (histaminergic) and alpha1 (adrenergic) receptors. A composed ratio of the APD affinity for diverse neurotransmitters involved in food intake (FI) regulation correlates with BWG as well. Endocrine/metabolic mechanisms, such as the activation of the hypothalamus-pituitary-adrenal axis, changes in insulin sensitivity (by conventional and atypical agents), hyperprolactinemia and gonadal dysfunction (by conventional APDs and risperidone) may also be involved. Importantly, patients with schizophrenia may have a genetically-based predisposition to appetite dysregulation, insulin resistance and endocrine imbalance involving gonadal steroids. Excessive BWG must be prevented or attenuated by proper drug selection, combining or switching agents, nutritional assistance and physical exercise. Amantadine. metformin and reboxetine proved to significantly lessen APD-induced BWG. Notwithstanding this, novel strategies are necessary to treat this side effect in a clinical population particularly prone to poor compliance and under a high risk of negative drug interaction.

[Advances in the molecular treatment of depression]. / Avances en la terapéutica molecular de la depresión.

AIMS: The objective of this study is to survey present and future antidepressant drug therapy based on the progress made in the field of biotechnology. DEVELOPMENT: The simplistic and mistaken view that one single system of neurotransmission is altered in depression and that there is, therefore, just one single treatment has changed. Molecular biology and Genetics have enabled us to determine other possible chemical alterations in the brain, beyond the sole participation of the monoaminergic modulation systems, which is the classical hypothesis. In this paper we describe the evidence for the relations between depression and the therapeutic effect the classical antidepressants have on: 1. The peptidergic system of the corticotropin-releasing hormone, cortisol and the functional state of its receptors; 2. Intracellular signalling systems such as cAMP on transcription factors like CREB and neurotrophins; 3. The immune system and cytosines; 4. Glutamate transmission; and 5. The neuropeptidergic system of substance P, neuroactive steroids and the neuroglia. This has allowed other biochemical hypotheses about depression and the possibility of new treatments to be put forward. CONCLUSIONS: We are still not certain about the exact cause or the processes that determine mental illnesses such as depression or how improvements are achieved with the antidepressants we currently have available. Nevertheless, biotechnology is expected to be a great help in advancing towards a better understanding of the interrelations between the nervous, immune and endocrine systems, with their intracellular cascades and final outcomes in genetic expression and protein function, in depression. This will enable more efficient, more selective and faster-acting drugs to be developed and, in the future and with the help of psychogenomics, even make it possible to produce tailor-made medication for each patient.

Avances en la terapéutica molecular de la depresión / Advances in the molecular treatment of depression

Objetivo. Revisar la terapéutica farmacológica antidepresiva presente y futura basada en los avances de la biotecnología. Desarrollo. La visión simplista y errónea de un único sistema neurotransmisor alterado en la depresión y, por tanto, un único tratamiento, ha cambiado. Las técnicas de la biología molecular y la genética han permitido conocer otras posibles alteraciones químicas en el cerebro, más allá de la única participación de los sistemas moduladores monoaminérgicos, la hipótesis clásica. Se describen las evidencias acerca de las relaciones entre la depresión y el efecto terapéutico de los antidepresivos clásicos con: a) El sistema peptidérgico de la hormona liberadora de la corticotropina, el cortisol y el estado funcional de sus receptores; b) Los sistemas de señalización intracelular como el AMPc sobre factores de transcripción como CREB y las neurotrofinas; c) El sistema inmune y las citocinas; d) La transmisión glutamatérgica, y e) El sistema neuropeptidérgico de la sustancia P, los esteroides neuroactivos y la glía. Esto ha permitido la emergencia de otras hipótesis bioquímicas sobre la depresión y la posibilidad de nuevos tratamientos. Conclusiones. Aunque hoy se sigue sin conocer con certeza la causa exacta ni los procesos que determinan las enfermedades mentales como la depresión, ni cómo se produce la mejoría con los antidepresivos disponibles, hay una gran esperanza de que, con la ayuda de la biotecnología, se avanzará hacia un mejor conocimiento de las interrelaciones entre los sistemas nervioso, inmune y endocrino, con sus cascadas intracelulares y sus consecuencias finales en la expresión genética y la función proteica en la depresión; ello permitirá desarrollar fármacos más efectivos, rápidos y selectivos que, en el futuro, con la ayuda de la psicogenómica, podrán incluso diseñarse para cada paciente (AU)

Aims. The objective of this study is to survey present and future antidepressant drug therapy based on the progress made in the field of biotechnology. Development. The simplistic and mistaken view that one single system of neurotransmission is altered in depression and that there is, therefore, just one single treatment has changed. Molecular biology and Genetics have enabled us to determine other possible chemical alterations in the brain, beyond the sole participation of the monoaminergic modulation systems, which is the classical hypothesis. In this paper we describe the evidence for the relations between depression and the therapeutic effect the classical antidepressants have on: 1. The peptidergic system of the corticotropin-releasing hormone, cortisol and the functional state of its receptors; 2. Intracellular signalling systems such as cAMP on transcription factors like CREB and neurotrophins; 3. The immune system and cytosines; 4. Glutamate transmission; and 5. The neuropeptidergic system of substance P, neuroactive steroids and the neuroglia. This has allowed other biochemical hypotheses about depression and the possibility of new treatments to be put forward. Conclusions. We are still not certain about the exact cause or the processes that determine mental illnesses such as depression or how improvements are achieved with the antidepressants we currently have available. Nevertheless, biotechnology is expected to be a great help in advancing towards a better understanding of the interrelations between the nervous, immune and endocrine systems, with their intracellular cascades and final outcomes in genetic expression and protein function, in depression. This will enable more efficient, more selective and faster-acting drugs to be developed and, in the future and with the help of psychogenomics, even make it possible to produce tailor-made medication for each patient (AU)

Biomedical applications of capillary electrophoresis with laser-induced fluorescence detection.

Capillary electrophoresis (CE) is a high-efficiency analytical technique that has had a great impact as a tool in biomedical research, clinical and forensic practice in the last ten years. Only in one of the applications, the DNA analysis, it has had an explosive exponential growth in the last few years. This impact is expressed in an enormous amount of CE articles and many reviews. The CE advantages with respect to other analytical techniques: the required very small sample volume, rapid analysis, great resolution power and low costs, have made this technique ideal for the analysis of a numerous endogenous and exogenous substances present in biological fluids. The different modes of CE have been coupled to different detection techniques such as UV-absorbance, electrochemical, mass spectrometry and laser-induced fluorescence detection (LIFD) to detect different nature and molecular size separated analytes. This review focuses mostly on the applications of CE-LIFD, to measure drugs and endogenous neuroactive substances such as amino acids and monoamines, especially in microdialysis samples from experimental animals and humans. CE-LIFD trends are discussed: automated faster analysis with capillary array systems, resolution power improvement, higher detection sensitivity, and CE systems miniaturization for extremely small sample volume, in order to make CE easier and affordable to the lab bench or the clinical bed.

Neutral amino acids monitoring in phenylketonuric plasma microdialysates using micellar electrokinetic chromatography and laser-induced fluorescence detection.

Neutral and non-polar amino acids such as phenylalanine (Phe), valine (Val), tyrosine (Tyr), threonine (Thre) and GABA are hard to resolve by capillary zone electrophoresis (CZE). Their separation is possible by adding a surfactant to the mobile phase. This method is called micellar electrokinetic chromatography (MEKC). We used MEKC with laser-induced fluorescence detection (LIFD) to separate and quantitate these amino acids in plasma microdialysates of patients with phenylketonuria (PKU). This disease is an inborn enzymatic defect with decreased conversion of Phe to Tyr that causes severe neurological damage and mental deterioration, which is diagnosed by measuring plasma Phe and Phe/Tyr ratio. The amino acids tested had linear concentration-signal relation. PKU patients had significantly higher Phe, lower Tyr, 21 times higher Phe/Tyr ratio and decreased values of Val and Thre than controls. These results show that microdialysis of biological fluids coupled with MEKC-LIFD is a convenient technique to measure neutral amino acids in clinical disorders such as PKU.

Medial prefrontal transection enhances social interaction. II: neurochemical studies.

Medial prefrontal cortex (MPFC) transection enhances social interaction in an open arena test. Social interaction enhances dopaminergic activity in the nucleus accumbens (NAC). In the present set of experiments, microdialysis probes were implanted in the NAC, and glutamate, gamma-aminobutyric acid (GABA) and dopamine (DA) were measured during electrical stimulation of the MPFC, after coronal transection caudal to the MPFC and after a systemic injection of amphetamine in transected rats. Electrical stimulation of the MPFC caused a transient enhancement of glutamate release in the NAC, no change in GABA levels and a long lasting increase in DA levels. Medial prefrontal transection did not change basal glutamate or GABA levels in the NAC, but increased basal DA levels. Amphetamine administration decreased GABA levels in medial prefrontal transected rats, had no effect on glutamate and increased DA levels more than in controls. The experiments suggest that glutamatergic activity in the accumbens decreases dopamine release. Medial prefrontal transection reduces glutamatergic tone and enhances dopamine release, which probably decreases GABAergic activity in the NAC. Presumably, GABA inhibition in the NAC enhances social interaction.

Use of intravenous microdialysis to monitor changes in serotonin release and metabolism induced by cisplatin in cancer patients: comparative effects of granisetron and ondansetron.

Serotonin [5-hydroxytryptamine (5-HT)] is involved in the production of emesis associated with cisplatin treatment. Serotonin released from intestinal enterochromaffin cells may act either directly on vagal afferents and/or pass to the circulation and stimulate central emetic centers. However, the role for circulating 5-HT has not been determined. In this study, i.v. microdialysis probes were used to investigate 1) cisplatin-induced changes in 5-HT release and metabolism assessed through changes in blood dialysate levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), 2) whether free 5-HT in blood increases after cisplatin, and 3) whether granisetron and ondansetron exert different effects on cisplatin-induced 5-HT release and metabolism. Control experiments conducted in 10 healthy volunteers revealed stable 5-HT and 5-HIAA dialysate levels for a period of 6 h. In patients with cancer (n = 16), baseline blood dialysate 5-HIAA concentrations averaged 2.98 +/- 0.38 ng/ml, which were equivalent to a total of 94 +/- 10 pg in the 30-min collection period at a flow rate of 1 microl/min. Cisplatin (89 +/- 2.9 mg of cisplatin/m(2)) produced a gradual increase in blood dialysate 5-HIAA levels (104 +/- 4% increase at 4 h). Increases in dialysate 5-HIAA were associated with increases in the urinary excretion of this metabolite. After cisplatin, dialysate 5-HIAA levels increased to 5.89 +/- 0.5 ng/ml in granisetron and to 5.27 +/- 0.9 ng/ml in ondansetron-treated patients (P >.1). Similar time courses and percentages of increase in blood dialysate and urinary 5-HIAA levels were observed in ondansetron- and granisetron-treated patients. Contrary to 5-HIAA, no significant increases in dialysate 5-HT were observed from 2 to 8 h after cisplatin either for the total group or for each of the groups separately. In conclusion, i.v. microdialysis probes coupled to HPLC-EC allowed the continuous monitoring of free-5-HT and 5-HIAA in blood. Cisplatin-induced increases in blood 5-HIAA were not associated with increases in 5-HT blood dialysates. These results argue against a possible action of free 5-HT in plasma on the chemoreceptor trigger zone (unprotected from the blood brain barrier) but support the view that 5-HT released within the intestinal wall triggers emesis after cisplatin. Our results argue against the view that at clinically effective doses, granisetron and ondansetron exert different actions on cisplatin-induced 5-HT release and metabolism.

Monitoring gamma-aminobutyric acid in human brain and plasma microdialysates using micellar electrokinetic chromatography and laser-induced fluorescence detection.

Due to its low electrophoretic mobility, few studies have been able to measure gamma aminobutyric acid (GABA) in biological samples by means of capillary zone electrophoresis. Nevertheless, in micellar electrokinetic chromatography (MEKC) by adding a surfactant to the mobile phase separation can be carried out on the basis of the partition coefficient of the molecules rather than their electrophoretic mobility. In the present study microdialysis coupled to MEKC with laser induced fluorescence detection was used to successfully monitor GABA from cerebrospinal fluid and plasma dialysates. Moreover, we monitored changes in extracellular GABA from a human brain. Microdialysis samples were collected from a Parkinson's disease patient undergoing a thallamotomy as part of her treatment. Significant decreases in extracellular GABA were detected during high frequency electrical stimulation and following a thermolesion of the thalamus. These results demonstrate the feasibility of MEKC coupled to laser-induced fluorescence detection in resolving neutral amino acids, specifically GABA, from different human body fluids.

Mechanism of the neuroleptic-induced obesity in female rats.

1. Obesity is an undesirable side effect of neuroleptics which affects 50% approximately of patients under a program of chronic administration. 2. An animal model of neuroleptic-induced obesity and hyperphagia has been developed in female rats treated chronically with sulpiride (20 mg/Kg/ip. for 21 days). However, it is unknown whether or not the hyperphagia is essential for the development of this type of obesity. 3. Sulpiride or vehicle was administered in two experimental conditions: in the first one, food was available in an amount which was three times the previous individual daily food intake; in the second one, the daily food provision was maintained at the individual daily average before starting the treatments. This way hyperphagia was prevented in half of the groups. Besides the body weight gain measurement in all the groups, the serum levels of estradiol, prolactin, glucose and lipids were assessed in the groups with unrestricted food intake. 4. Food restriction prevented the sulpiride-induced weight gain, even though the rats displayed a permanent diestrus which suggests an hyperprolactinemia-induced impairment in the balance of the reproductive hormones that may promote weight gain. However, the basal levels of estradiol were not affected by sulpiride. 5. The high density cholesterol was significantly increased by sulpiride, and the serum glucose levels were significantly decreased, however these changes were only detected during the first week of treatment. 6. The decrease in the serum glucose levels may be an early consequence of hyperinsulinemia. 7. Neuroleptic-induced obesity in rats appears to mimic energy intake, endocrine status and carbohydrate metabolism in humans under chronic neuroleptic administration. However, these rodents did not display the typical changes in blood lipids observed in human obesity.

Plasma serotonin monitoring by blood microdialysis coupled to high-performance liquid chromatography with electrochemical detection in humans.

Plasma serotonin (5-HT) active pool was monitored in male volunteers by intravenous microdialysis coupled to HPLC-EC with 98.6% efficient probes. 5-HT was monitored from 60 min before to 360 min after an oral dose of fluoxetine, a 5-HT uptake inhibitor, or vehicle. The basal values were within nanomolar range (0.55 to 4.6 ng/ml). After administration of fluoxetine, there was a significant increment of 5-HT with respect to controls. These results showed that intravenous microdialysis is an alternative efficient technique to monitor endogenous unbound 5-HT changes in plasma without extracting blood or sample pretreatment procedures before the chemical analysis.

New approaches in clinical chemistry: on-line analyte concentration and microreaction capillary electrophoresis for the determination of drugs, metabolic intermediates, and biopolymers in biological fluids.

The use of capillary electrophoresis (CE) for clinically relevant assays is attractive since it often presents many advantages over contemporary methods. The small-diameter tubing that holds the separation medium has led to the development of multicapillary instruments, and simultaneous sample analysis. Furthermore, CE is compatible with a wide range of detectors, including UV-Vis, fluorescence, laser-induced fluorescence, electrochemistry, mass spectrometry, radiometric, and more recently nuclear magnetic resonance, and laser-induced circular dichroism systems. Selection of an appropriate detector can yield highly specific analyte detection with good mass sensitivity. Another attractive feature of CE is the low consumption of sample and reagents. However, it is paradoxical that this advantage also leads to severe limitation, namely poor concentration sensitivity. Often high analyte concentrations are required in order to have injection of sufficient material for detection. In this regard, a series of devices that are broadly termed 'analyte concentrators' have been developed for analyte preconcentration on-line with the CE capillary. These devices have been used primarily for non-specific analyte preconcentration using packing material of the C18 type. Alternatively, the use of very specific antibody-containing cartridges and enzyme-immobilized microreactors have been demonstrated. In the current report, we review the likely impact of the technology of capillary electrophoresis and the role of the CE analyte concentrator-microreactor on the analysis of biomolecules, present on complex matrices, in a clinical laboratory. Specific examples of the direct analysis of physiologically-derived fluids and microdialysates are presented, and a personal view of the future of CE in the clinical environment is given.

Changes in dopamine and acetylcholine release in the rat lateral hypothalamus during deprivation-induced drinking.

Neurochemical changes in the rat lateral hypothalamus during drinking were assessed in 20 min sampling intervals, using in vivo brain microdialysis. Water-deprived animals drank (11 +/- 1 ml) during the hour that water was available. Drinking was maximal (7.8 +/- 0.7 ml) during the first 20 min after water presentation and minimal during the last 20 min (0.5 +/- 0.4 ml). There was a local enhancement in DA turnover evidenced by an increase in the extracellular levels of dopamine (DA) (155 +/- 47% during the second sample after water presentation as compared to predrinking levels) and dihydroxyphenyl acetic acid (DOPAC) (132 +/- 9.7% in the sample that followed water removal). There was also an initial increase in the acetylcholine (ACh) release (145.1 +/- 21.7%) during the first 20 min after water presentation followed by a reduction (50.12 +/- 18%) 20 min later. These changes are congruous with previously published results suggesting that both neurochemical systems are involved in the regulation of water intake. Considering that the exogenous administration of cholinergic drugs in this hypothalamic area elicits drinking, the initial increase in ACh release could be interpreted as one of the neurochemical events driving this behavior. Since the local blockade of D2 receptors has been shown to result in drinking the progressive increase in DA turnover detected in this study, as well as the concomitant reduction in ACh release, could be involved in drinking attenuation.

Amantadine in the treatment of neuroleptic-induced obesity in rats: behavioral, endocrine and neurochemical correlates.

The efficacy of the antiviral agent Amantadine (AM, 5-100 mg/kg/sc, ip or intrahypothalamically, 12.5-100 micrograms bilaterally) in influencing body weight and food intake in drug-free rats, and in preventing neuroleptic-induced weight gain, was assessed in adult female rats. In drug-free rats, acute administration of systemic AM or directly injected in the lateral hypothalamus (LH) displayed a significant dose-dependent anorectic effect (p < 0.001). This effect could be mediated by the brain monoaminergic system, because systemic or local injections of AM increased dopamine and serotonin overflow in the nucleus accumbens and in the LH. Chronic administration of AM significantly decreased body weight gain in drug-free rats only at the dose of 100 mg/kg/sc. Similarly, obesity induced by the neuroleptic drug sulpiride (SUL, 20 mg/kg/ip for 21 days) was prevented by AM only at the dose of 100 mg/kg. AM did not prevent SUL-induced hyperprolactinemia, disruption of the vaginal cycle and a decrement in the weight of the uterus and ovaries at any dosage. This lack of efficacy of AM contrasts with that of bromocriptine, which completely prevented SUL-induced weight gain and hyperprolactinemia. The results show that despite a potent acute anorectic effect, AM displays a weak antagonistic action on SUL-induced obesity in rats, in contrast to the preliminary results obtained in humans. As AM metabolism differs in humans and rats, additional research is needed before its systematic testing in counteracting neuroleptic-induced obesity in patients with mental disorders.

Blood microdialysis in humans: a new method for monitoring plasma compounds.

A new venous microdialysis probe for humans was developed. The active area was made with cellulose membrane (220 mm outside diameter, length 20 mm, and 6000 molecular weight cut off). Glucose measurements were used to test it. The relative recovery was 50% in dialysates obtained in vitro, the step response was 91.8% in the first 2 min. The in vivo recovery was 65.8% obtained by the no net flux method, with the probe placed in the cubital vein of the subjects arms. Corrected glucose in dialysates was non significantly different from plasma glucose simultaneously collected. In healthy male volunteers from 18 to 37 years of age, mean 22.1 years, the glucose levels in the blood dialysates were measured every 30 min, 60 min before and 150 min after an oral load of 75 g of glucose or vehicle. Glucose increased significantly after the load. The differences with the control group were significant at 60 and 90 min after the treatment. The results showed the easy and safe application of this technique to monitor endogenous and exogenous compounds in the extracellular compartment of blood in out patients.

Effects of the antipsychotic drug sulpiride on reproductive hormones in healthy men: relationship with body weight regulation.

Metabolic and endocrine abnormalities secondary to hyperprolactinemia, particularly hypogonadism, may be involved in the excessive body weight gain observed during treatment with antipsychotic drugs. The present study was conducted in healthy men in order to detect an endocrine imbalance secondary to antipsychotic drug administration, which, if sustained in the long term, might be involved in the development of obesity. Sulpiride (200 mg daily for 30 days) or placebo was nonblindly administered, and body weight gain was correlated with the serum levels of prolactin, luteinizing hormone, follicle-stimulating hormone, estradiol, free testosterone, thyrotropic hormone, free tetraiodothyroxine, cortisol, dehydroepiandrosterone sulphate (DHEA-S), and the ratios estradiol/testosterone and testosterone/DHEA-S; the blood lipids were also assessed. Body weight gain and the serum levels of prolactin were significantly increased by sulpiride; in addition, a significant positive correlation was observed between prolactin levels and body weight gain. Other endocrine parameters were not significantly affected by the drug. These short-term results show that in healthy men, body weight can be increased by antipsychotic drug administration; this effect may be related to hyperprolactinemia alone, since other endocrine parameters were normal at the time of treatment. A more prolonged treatment with antipsychotic agents might be required to observe the alterations in gonadal and adrenal steroids often detected in subjects with primary obesity.

Effects of the antipsychotic drug sulpiride on reproductive hormones in healthy premenopausal women: relationship with body weight regulation.

Metabolic and endocrine abnormalities secondary to hyperprolactinemia, such as hypogonadism and hyperandrogenicity, may be involved in the excessive body weight gain induced by antipsychotic drugs in women. The present study was conducted in healthy premenopausal women, in order to detect an endocrine imbalance secondary to antipsychotic drug administration, which, if sustained in the long term, might be involved in the development of obesity. After a control menstrual cycle, sulpiride (200 mg/day) or placebo was nonblindly administered for 28 days; blood lipids and the serum levels of the following hormones which are involved in body weight regulation were assessed at days 3, 10, 20 and 26 of the cycle: prolactin (PRL), 17-beta estradiol (E2), progesterone (P4), follicle stimulating hormone (FSH), luteinizing hormone (LH), free testosterone (T5), dehydroepiandrosterone sulfate (DHEAS), cortisol, tyrotropic hormone (TSH), tetraiodothyroxine (T4), and the areas under the insulin and glucose tolerance curve. During sulpiride administration, the following changes were observed when compared to placebo administration: PRL levels were significantly increased; E2 levels were significantly reduced at days 10 and 20; P4 levels were significantly reduced at day 20, and the area under the glucose tolerance curve was significantly increased. The other variables were not significantly affected. The body weight gain was higher during sulpiride than during placebo administration, but it did not reach statistical significance, perhaps because the period of treatment was too short. The decrease in the serum levels of E2 during sulpiride administration is probably secondary to hyperprolactinemia. It affects the E2/T5 ratio in the direction of increasing the androgenic activity, as observed in women with well-established obesity. This effect, along with a genetic predisposition, increased appetite, hypoactivity and ignorance of proper dietary habits, may explain the excessive weight gain and obesity observed in women during chronic treatment with sulpiride and other antipsychotic agents.

Capillary electrophoresis-laser-induced fluorescence detection of amphetamine in the brain.

Prefrontal cortex microdialysis was done in rats that had received intraperitoneal amphetamine (AMPH). Samples were derivatized with 10(-4) M fluorescein isothiocyanate and incubated for 18 h. AMPH was separated by capillary electrophoresis (CE) and detected by laser-induced fluorescence detection (LIFD) from 30 to 150 min after injection. The limit of mass detection was 3 amol, which is three orders of magnitude lower than that in gas chromatography-mass spectrometry, and the limit of concentration detection was 3 x 10(-9) M. The results showed that CE-LIFD is a good method for detecting AMPH in brain dialysates of rats.

Use of sonography in diagnosing acute appendicitis: comparison of a teaching hospital and a community hospital.

RATIONALE AND OBJECTIVES: We examined patterns of use of sonography in the workup of appendicitis at two hospitals: a 715-bed university-affiliated teaching hospital and a 240-bed nonteaching hospital. In light of increasing concern over the use of health care dollars, we wanted to determine whether the use of sonography in the workup of appendicitis would be more frequent at a teaching than at a nonteaching hospital. METHODS: We examined all cases of appendicitis seen in the emergency room of the teaching hospital in 1993 and all cases of appendicitis seen in the emergency room of the nonteaching hospital in 1992-1993. Exclusionary criteria included pregnancy, altered mental status, or multiple discharge diagnoses. The diagnosis of appendicitis was verified by pathology reports. RESULTS: At the teaching hospital, the use of sonography was 38.5% (65 of 169); at the nonteaching hospital, sonography usage was 39.4% (61 of 155). CONCLUSION: There appears to be no significant difference between teaching and nonteaching hospitals in the frequency of use of sonography in diagnosing patients with appendicitis.

Simultaneous brain and blood microdialysis study with a new removable venous probe. Serotonin and 5-hydroxyindolacetic acid changes after D-norfenfluramine or fluoxetine.

A removable intravenous microdialysis probe was developed and simultaneously used with a removable microdialysis probe placed in the lateral hypothalamus (LH). Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) changes in blood and brain dialysates were measured by HPLC-EC after an i.p. injection of 5 mg/kg d-norfenfluramine (dNF) or 10 mg/kg fluoxetine (FLU) in freely moving rats. 5-HT in the LH significantly increased after both drugs, but the rise was larger and faster with dNF [F(7,28)=4.0 p<0.05] than with FLU [F(5,20)=5.0 p<0.01]. By contrast, in venous blood 5-HT increased after FLU [F(5,20)=2.96 p<0.05] but not after dNF. 5-HIAA after both drugs continued decreasing significantly in the LH [dNF F(7,28)=11.4 p<0.01; FLU F(5,20)=22.8 p<0.01], but it did not change in blood. Simultaneous dialysis in brain and blood allowed evaluation of the differential effects of dNF and FLU on 5-HT and 5-HIAA in the two places. Removable venous probes prevented the inflammatory reaction that may occur around permanently implanted probes, and the dialysis could be more efficient and with less risk of clogging.

Hypothalamic neuropeptide Y, its gene expression and receptor activity: relation to circulating corticosterone in adrenalectomized rats.

Previous evidence has suggested a possible relationship between the adrenal steroid, corticosterone (CORT) and neuropeptide Y (NPY) in the brain. To provide a more systematic analysis of this interaction, the present study employed a variety of techniques, including in situ hybridization to measure NPY gene expression, radioimmunoassay to examine peptide levels and radioligand [125I]peptide YY (PYY) binding for analysis of peptide receptors. The results show that adrenalectomy (ADX), which caused a decline in CORT to levels < 0.3 micrograms %, has generally little impact on the hypothalamic NPY projection system under normal, basal conditions. This includes peptide gene expression or content in the area of its cell bodies (arcuate nucleus, ARC), in addition to peptide binding at its receptor sites. While it also includes peptide content at most hypothalamic terminal sites, there are three notable exceptions, namely, the medial paraventricular (PVN) and dorsomedial nuclei and medial preoptic area, where NPY nerve terminals and glucocorticoid receptors are particularly dense and the decline in CORT through ADX markedly reduces NPY content. In contrast, evidence obtained from CORT replacement in ADX rats shows that this steroid has profound impact on all components of the hypothalamic NPY system. This peptide-steroid interaction is apparent at the level of the cell body (ARC), as well as at the nerve terminal or receptor site (PVN and ARC), where CORT levels > 10 micrograms % strongly potentiate NPY gene expression, peptide content and radioligand binding. These and other findings suggest that this CORT-NPY interaction in the hypothalamus occurs physiologically under conditions, e.g., at the onset of the active feeding cycle, when circulating CORT normally rises.